chr8-139731094-A-C

Position:

chr8-139731094-A-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001160372.4(TRAPPC9):c.3414T>G(p.Ser1138Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000982 in 1,613,644 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00070 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 2 hom. )

Consequence

TRAPPC9
NM_001160372.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 0.0490

Variant links:

Genes affected

TRAPPC9 (HGNC:30832): (trafficking protein particle complex subunit 9) This gene encodes a protein that likely plays a role in NF-kappa-B signaling. Mutations in this gene have been associated with autosomal-recessive cognitive disability. Alternatively spliced transcript variants have been described.[provided by RefSeq, Feb 2010]

TRAPPC9 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013682127).

BP6

Variant 8-139731094-A-C is Benign according to our data. Variant chr8-139731094-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 362060.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000696 (106/152306) while in subpopulation NFE AF= 0.00101 (69/68004). AF 95% confidence interval is 0.000822. There are 0 homozygotes in gnomad4. There are 51 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRAPPC9	NM_001160372.4 linkuse as main transcript	c.3414T>G	p.Ser1138Arg	missense_variant	23/23	ENST00000438773.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRAPPC9	ENST00000438773.4 linkuse as main transcript	c.3414T>G	p.Ser1138Arg	missense_variant	23/23	1	NM_001160372.4	P1	Q96Q05-1

Frequencies

GnomAD3 genomes

AF:

0.000697

AC:

106

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00264

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00101

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000879

AC:

220

AN:

250296

Hom.:

AF XY:

0.00100

AC XY:

136

AN XY:

135618

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00260

Gnomad NFE exome

AF:

0.00135

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.00101

AC:

1478

AN:

1461338

Hom.:

Cov.:

AF XY:

0.00103

AC XY:

747

AN XY:

726992

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00275

Gnomad4 NFE exome

AF:

0.00115

Gnomad4 OTH exome

AF:

0.000795

GnomAD4 genome

AF:

0.000696

AC:

106

AN:

152306

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00264

Gnomad4 NFE

AF:

0.00101

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000700

Hom.:

Bravo

AF:

0.000525

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000947

AC:

115

EpiCase

AF:

0.000818

EpiControl

AF:

0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2017

The p.S1236R variant (also known as c.3708T>G), located in coding exon 23 of the TRAPPC9 gene, results from a T to G substitution at nucleotide position 3708. The serine at codon 1236 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Intellectual Disability, Recessive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Intellectual disability

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 24, 2015

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.12

CADD

Benign

9.8

DANN

Benign

0.96

DEOGEN2

Benign

0.035

T;T;.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.87

.;.;D;D

M_CAP

Benign

0.034

MetaRNN

Benign

0.014

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.0

L;L;.;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.6

.;N;N;.

REVEL

Uncertain

0.31

Sift

Benign

0.047

.;D;D;.

Sift4G

Uncertain

0.053

.;T;D;.

Polyphen

0.44

B;B;P;B

Vest4

0.58, 0.60

MutPred

0.50

Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);.;Gain of sheet (P = 0.0344);

MVP

0.061

MPC

0.43

ClinPred

0.053

GERP RS

-5.0

Varity_R

0.33

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over